Field of the Invention
This invention is directed to novel organic compounds and is more specifically concerned with aminotriazolobenzodiazepines of the formulae below and methods of production thereof.
The novel compounds and the processes therefor can be illustratively represented as follows: ##STR2##
The products in which R is hydrogen as well as methyl or ethyl are produced by a Scheme B process ##STR3## wherein R is hydrogen, methyl or ethyl; wherein R' and R" are hydrogen, alkyl of 1 to 3 carbon atoms, inclusive; wherein R'" is alkyl defined as above, wherein R.sub.1 is hydrogen or methyl defined as above; and wherein R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are selected from the group consisting of hydrogen, alkyl defined as above, halogen, nitro, trifluoromethyl, and alkoxy and alkylthio, in which the carbon chain moiety is of 1 to 3 carbon atoms, inclusive.
The process of Method A of this invention comprises: treating an ester of formula I with ammonia or an amine at a temperature between 25.degree.-200.degree. C. in an organic solvent to obtain an amide of formula II; reducing the amide with borane (B.sub.2 H.sub.6) or aluminum hydride (AlH.sub. 3) in an organic solvent between room temperature and the reflux temperature of the reaction mixture to obtain the amine III of the formula above and oxidizing III e.g. with an oxidizing agent selected from the group consisting of dichlorodicyanoquinone, manganese dioxide, ruthenium tetroxide or with diethylazodicarboxylate to obtain the benzodiazepine of formula IV.
The process of method B of this invention comprises: treating a hydrazino compound of formula V with a reactive derivative of a .beta.-phthalimidocarboxylic acid (e.g. the acid chloride or bromide) of the formula: ##STR4## wherein R is defined as above, or with the free acid and a dehydrating agent e.g. carbonyldimidazole and warming the resulting product in a solvent such as acetic acid, to obtain the corresponding compound VI, treating VI with hydrazine to obtain VII and alkylating VII, if desired to obtain VIII. If R' and R" are not identical this reaction must be carried out with one equivalent of aldehyde to one equivalent of compound VII and if desired with another acid aldehyde to obtain an amine VIII with two different alkyl groups. Compound VIII can be reduced with diborane to give the saturated compound IX.
The active compounds of this invention can be presented by the summary formula X: ##STR5## wherein R is hydrogen, methyl, or ethyl; wherein R' and R" are hydrogen or alkyl of 1 to 3 carbon atoms, inclusive; wherein R.sub.1 is hydrogen or methyl defined as above; wherein R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are selected from the group consisting of hydrogen, alkyl defined as above, halogen, nitro, trifluoromethyl, and alkoxy and alkylthio, in which the carbon chain moiety is of 1 to 3 carbon atoms, inclusive, and in which the 5 to 6 nitrogen-carbon linkage is selected from the group consisting of double bonds and single bonds, and the pharmacologically acceptable acid addition salts thereof.
The more desirable products have the formula XI ##STR6## wherein R.sub.6 is hydrogen or methyl; wherein R' and R" are hydrogen or alkyl to 1 to 3 carbon atoms, inclusive; wherein R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are selected from the group consisting of hydrogen, halogen, nitro, and trifluoromethyl, and the pharmacologically acceptable acid addition salts thereof.
Most preferred are the compounds of formula XII: ##STR7## wherein R.sub.6 is hydrogen or methyl; wherein R' and R" are hydrogen or alkyl of 1 to 3 carbon atoms, inclusive; wherein R.sub.2 and R.sub.4 are selected from the group consisting of hydrogen and chlorine, and the pharmacologically acceptable acid addition salts thereof.